Cascaded gas chromatographs (CGCs) with individual temperature control and gas analysis systems using same

ABSTRACT

The disclosure describes a cascaded gas chromatograph including a first gas chromatograph having a first temperature control and a second gas chromatograph coupled to the first gas chromatograph. The first and second chromatographs have individual temperature controls that can be controlled independently of each other. Other embodiments are disclosed and claimed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation under 35 U.S.C. §120 of U.S.application Ser. No. 12/830,682, filed 6 Jul. 2010 and still pending,and also claims priority under 35 U.S.C. §119(e) to U.S. ProvisionalPatent Application No. 61/223,678, filed 7 Jul. 2009.

TECHNICAL FIELD

The present invention relates generally to cascaded gas chromatograph(CGCs) and in particular, but not exclusively, to CGCs including gaschromatographs with individual temperature control and to gas analysissystems using such CGCs.

BACKGROUND

Gas analysis can be an important means for detecting the presence andconcentration of certain chemicals in the gas and determining themeaning of the particular combination of chemicals present. In healthcare, for example, the presence of certain volatile organic compounds(VOCs) in exhaled human breath are correlated to certain diseases, suchas pneumonia, pulmonary tuberculosis (TB), asthma, lung cancer, liverdiseases, kidney diseases, etc. The correlations are especiallyevidential for lung-related diseases. In other applications, gasanalysis can be used to determine the presence of dangerous substancesincompatible with human presence, such as methane, carbon monoxide orcarbon dioxide in a mine.

Current gas analytical systems still rely heavily on large and expensivelaboratory instruments, such as gas chromatography (GC) and massspectrometry (MS). Most of these instruments (mass spectrometers inparticular) have operational characteristics that prevent significantreductions in their size, meaning that current gas analysis systems arelarge and expensive bench devices. In addition to being expensive andunwieldy, the large size of current gas analysis devices makeswidespread use of these instruments impossible.

GC column coatings are usually optimized for specific temperatures andchemicals, so that no single GC can separate a large array of chemicals,even by varying its temperature. Because existing GCs are large, heavyunits housed in labs, a carrier gas with many chemicals may need to besent to multiple locations for separation, which substantially increasescost.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting and non-exhaustive embodiments of the present invention aredescribed with reference to the following figures, wherein likereference numerals refer to like parts throughout the various viewsunless otherwise specified.

FIG. 1A is a side elevation drawing of an embodiment of a gas analysisdevice.

FIG. 1B is a plan view of the embodiment of a gas analysis device shownin FIG. 1.

FIG. 2A is a cross-sectional elevation drawing of an embodiment of aMEMS pre-concentrator that can be used in the embodiment of a gasanalysis device shown in FIGS. 1A-1B.

FIG. 2B is a cross-sectional elevation drawing of an alternativeembodiment of a MEMS pre-concentrator that can be used in the embodimentof a gas analysis device shown in FIGS. 1A-1B.

FIG. 3A is a plan view drawing of an embodiment of a MEMS gaschromatograph that can be used in the embodiment of a gas analysisdevice shown in FIGS. 1A-1B.

FIG. 3B is a cross-sectional elevation drawing of the embodiment of aMEMS gas chromatograph shown in FIG. 3A, taken substantially alongsection line B-B.

FIG. 3C is a cross-sectional elevation drawing of an alternativeembodiment of the MEMS gas chromatograph shown in FIG. 3B.

FIG. 3D is a plan view of an alternative embodiment of a gaschromatograph that can be used in the embodiment of a gas analysisdevice shown in FIGS. 1A-1B.

FIG. 3E is a cross-sectional elevation drawing of the embodiment of agas chromatograph shown in FIG. 3D.

FIG. 4A is a plan view drawing of an embodiment of a detector array thatcan be used in the embodiment of a gas analysis device of FIGS. 1A-1B.

FIG. 4B is a cross-sectional elevation drawing of the embodiment of adetector array shown in FIG. 4A, taken substantially along section lineB-B.

FIG. 5 is a schematic diagram of an alternative embodiment of a gasanalysis device and an embodiment of a system using the embodiment ofthe gas analysis device.

FIG. 6 is a schematic diagram of another alternative embodiment of a gasanalysis device and an embodiment of a system using the embodiment ofthe gas analysis device.

FIG. 7 is a plan-view schematic diagram of an additional alternativeembodiment of a gas analysis device.

FIG. 8 is a plan-view schematic diagram of an additional alternativeembodiment of a gas analysis device.

FIG. 9 is a plan-view schematic diagram of an additional alternativeembodiment of a gas analysis device.

FIG. 10A is a plan-view schematic of an embodiment of a cascaded gaschromatograph.

FIG. 10B is a plan-view schematic of an alternative embodiment of acascaded gas chromatograph.

FIG. 10C is a plan-view schematic of another alternative embodiment of acascaded gas chromatograph.

FIG. 10D is a plan-view schematic of another alternative embodiment of acascaded gas chromatograph

FIG. 10E is a plan-view schematic of another alternative embodiment of acascaded gas chromatograph.

FIG. 10F is a plan-view schematic of another alternative embodiment of acascaded gas chromatograph.

FIG. 11A is a plan-view schematic of an embodiment of a cascaded gaschromatograph.

FIG. 11B is a plan-view schematic of an alternative embodiment of acascaded gas chromatograph.

FIG. 11C is a plan-view schematic of another alternative embodiment of acascaded gas chromatograph.

FIGS. 12A-12C are schematic drawings of embodiments of cascaded gaschromatographs using conventional gas chromatographs.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS

Embodiments of an apparatus, process and system for gas analysis inpoint-of-care medical applications are described herein. In thefollowing description, numerous specific details are described toprovide a thorough understanding of embodiments of the invention. Oneskilled in the relevant art will recognize, however, that the inventioncan be practiced without one or more of the specific details, or withother methods, components, materials, etc. In other instances,well-known structures, materials, or operations are not shown ordescribed in detail but are nonetheless encompassed within the scope ofthe invention.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure, orcharacteristic described in connection with the embodiment is includedin at least one embodiment of the present invention. Thus, appearancesof the phrases “in one embodiment” or “in an embodiment” in thisspecification do not necessarily all refer to the same embodiment.Furthermore, the particular features, structures, or characteristics maybe combined in any suitable manner in one or more embodiments.

FIGS. 1A and 1B together illustrate an embodiment of a small scale(e.g., handheld) gas analysis device 100. Device 100 includes asubstrate 102 on which are mounted a fluid handling assembly 101, acontroller 126 coupled to the individual elements within fluid handlingassembly 101, and a reading and analysis circuit 128 coupled to detectorarray 110 and to controller 126. The embodiment shown in the figuresillustrates one possible arrangement of the elements on substrate 102,but in other embodiments the elements can, of course, be arranged on thesubstrate differently.

Substrate 102 can be any kind of substrate that provides the requiredphysical support and communication connections for the elements ofdevice 100. In one embodiment, substrate 102 can be a printed circuitboard (PCB) of the single-layer variety with conductive traces on itssurface, but in other embodiments it can be a PCB of the multi-layervariety with conductive traces in the interior of the circuit board. Inother embodiments, for example an embodiment where device 100 is builtas a monolithic system on a single die, substrate 102 can be chip orwafer made of silicon or some other semiconductor. In still otherembodiments, substrate 102 can also be a chip or wafer in which opticalwaveguides can be formed to support optical communication between thecomponents of device 100.

Fluid handling assembly 101 includes a filter and valve assembly 104, apre-concentrator 106, a gas chromatograph 108, a detector array 110 anda pump 112. Elements 104-112 are fluidly coupled in series: filter andvalve assembly 104 is fluidly coupled to pre-concentrator 106 by fluidconnection 116, pre-concentrator 106 is fluidly coupled to gaschromatograph 108 by fluid connection 118, gas chromatograph 108 isfluidly coupled to detector array 110 by fluid connection 120, anddetector array 110 is coupled to pump 112 by fluid connection 122. Asfurther described below, in one embodiment of device 100 elements104-112 can be micro-electro-mechanical (MEMS) elements or MEMS-basedelements, meaning that some parts of each device can be MEMS and otherparts not. In other embodiments of device 100, some or all of elements104-112 need not be MEMS or MEMS-based, but can instead be some non-MEMSchip scale device.

As indicated by the arrows in the figures, the fluid connections betweenelements 104-112 allow a fluid (e.g., one or more gases) to enter filterand valve assembly 104 through inlet 114, flow though elements 104-112,and finally exit pump 112 through outlet 124. Fluid handling assembly101 also includes a shroud or cover 112 that protects individualelements 104-112. In the illustrated embodiment, channels formed inshroud 112 provide the fluid connections between the elements, but inother embodiments the fluid connections between elements can be providedby other means, such as tubing. In still other embodiments shroud 112can be omitted.

Filter and valve assembly 104 includes an inlet 114 and an outletcoupled to fluid connection 116 such that fluid exiting filter and valveassembly 104 flows into pre-concentrator 106. Filter and valve assembly104 includes a filter to remove particulates from fluid entering throughinlet 114. In embodiments of device 100 where one or more of elements104-112 is a MEMS element, the small scale of parts within the MEMSelements means that fluid entering through inlet 114 might need to befiltered to remove these particles so that the particles do not enterthe MEMS elements and either them or render them inoperative. Inembodiments of device 100 that include no MEMS components, or wherefluid entering inlet 114 contains no particles, for instance because ithas been pre-filtered externally to device 100, the filter portion offilter and valve assembly 104 can be omitted.

Filter and valve assembly 104 also includes a valve so that further flowthrough inlet 114 into fluid handling assembly 101 can be stopped oncesufficient fluid has passed through the device. Stopping further flowthrough inlet 114 prevents dilution of fluids that will flow out ofpre-concentrator 106 during later operation of device 100 (seedescription of operation below). In other embodiments, filter and valveassembly 104 can also include a de-humidifier to remove water vapor fromthe fluid entering through inlet 114, thus improving the accuracy andsensitivity of device 100.

Pre-concentrator 106 includes an inlet coupled to fluid connection 116and an outlet coupled to fluid connection 118. Pre-concentrator 106receives fluid from filter and valve assembly 104 through fluidconnection 116 and outputs fluid to gas chromatograph 108 through fluidconnection 118. As fluid flows through pre-concentrator 106, thepre-concentrator absorbs certain chemicals from the passing fluid, thusconcentrating those chemicals for later separation and detection. In oneembodiment of device 100 pre-concentrator 106 can be a MEMSpre-concentrator, but in other embodiments pre-concentrator 106 can be anon-MEMS chip scale device. Further details of an embodiment of a MEMSpre-concentrator are described below in connection with FIG. 2.

Gas chromatograph 108 includes an inlet coupled to fluid connection 118and an outlet coupled to fluid connection 120. Gas chromatograph 108receives fluid from pre-concentrator 106 through fluid connection 118and outputs fluid to detector array 110 through fluid connection 120. Asfluid received from pre-concentrator 106 flows through gas chromatograph108, individual chemicals in the fluid received from thepre-concentrator are separated from each other in the time domain forlater input into detector array 110. In one embodiment of device 100 gaschromatograph 108 can be a MEMS gas chromatograph, but in otherembodiments gas chromatograph 108 can be a non-MEMS chip scale device.Further details of an embodiment of a MEMS gas chromatograph 108 aredescribed below in connection with FIGS. 3A-3C. Although shown in thedrawing as a single chromatograph, in other embodiments gaschromatograph 108 can include multiple individual chromatographs, suchas any of the cascaded gas chromatographs shown in FIG. 10A et seq. Inan embodiment in which gas chromatograph 108 includes multiplechromatographs, it can be necessary to adjust the number of downstreamand/or upstream components in device 100 to coincide with the input oroutput configuration of the gas chromatograph. For instance, if thecascaded chromatograph 1050 shown in FIG. 10C is used as chromatograph108 in device 100, it can be necessary to adjust the number of detectorarrays 110, pumps 112, and so forth, to correspond to the number ofoutputs of chromatograph 1050.

Detector array 110 includes an inlet coupled to fluid connection 120 andan outlet coupled fluid connection 122. Detector array 110 receivesfluid from gas chromatograph 108 through fluid connection 120 andoutputs fluid to pump 112 through fluid connection 122. As fluid flowsthrough detector array 110, the chemicals that were time-domainseparated by gas chromatograph 108 enter the detector array and theirpresence and/or concentration is sensed by sensors within the detectorarray. In one embodiment of device 100 detector array 110 can be a MEMSdetector array, but in other embodiments detector array 110 can be anon-MEMS chip scale device. Further details of an embodiment of adetector array 110 are described below in connection with FIG. 4.Although shown in the figure as a single detector array, in otherembodiments detector array 110 can actually include multiple detectorarrays. For example, in an embodiment where gas chromatograph 108 is acascaded configuration made up of several individual chromatographs,such as cascaded chromatograph 1050 shown in FIG. 10C, it can benecessary to adjust the number of detector arrays to match the outputconfiguration of the cascaded chromatographs.

Pump 112 includes an inlet coupled to fluid connection 122, as well asan outlet coupled to an exhaust 124, such that pump 112 draws fluid fromdetector array 110 through fluid connections 122 and returns it to theatmosphere through exhaust 124. Pump 112 can be any kind of pump thatmeets the size and form factor requirements of device 100, provides thedesired flow rate and flow rate control, and has adequate reliability(i.e., adequate mean time between failures (MTBF)). In one embodiment,pump 112 can be a MEMS or MEMS-based pump, but in other embodiments itcan be another type of pump. Examples of pumps that can be used includesmall axial pumps (e.g., fans), piston pumps, and electro-osmotic pumps.Although shown in the figure as a single pump, in other embodiments pump112 can actually be made up of multiple pumps. For example, in anembodiment where gas chromatograph 108 is a cascaded configuration madeup of several individual chromatographs, such as cascaded chromatograph1050 shown in FIG. 10C, it can be necessary to adjust the number ofpumps to match the output configuration of the cascaded chromatographs.

Controller 126 is communicatively coupled to the individual elementswithin fluid handling assembly 101 such that it can send control signalsand/or receive feedback signals from the individual elements. In oneembodiment, controller 126 can be an application-specific integratedcircuit (ASIC) designed specifically for the task, for example a CMOScontroller including processing, volatile and/or non-volatile storage,memory and communication circuits, as well as associated logic tocontrol the various circuits and communicate externally to the elementsof fluid handling assembly 101. In other embodiments, however,controller 126 can instead be a general-purpose microprocessor in whichthe control functions are implemented in software. In the illustratedembodiment controller 126 is electrically coupled to the individualelements within fluid handling assembly 101 by conductive traces 130 onthe surface or in the interior of substrate 102, but in otherembodiments controller 126 can be coupled to the elements by othermeans, such as optical.

Readout and analysis circuit 128 is coupled to an output of detectorarray 110 such that it can receive data signals from individual sensorswithin detector array 110 and process and analyze these data signals. Inone embodiment, readout and analysis circuit 128 can be anapplication-specific integrated circuit (ASIC) designed specifically forthe task, such as a CMOS controller including processing, volatileand/or non-volatile storage, memory and communication circuits, as wellas associated logic to control the various circuits and communicateexternally. In other embodiments, however, readout and analysis circuit128 can instead be a general-purpose microprocessor in which the controlfunctions are implemented in software. In some embodiments readout andanalysis circuit 128 can also include signal conditioning and processingelements such as amplifiers, filters, analog-to-digital converters,etc., for both pre-processing of data signals received from detectorarray 110 and post-processing of data generated or extracted from thereceived data by readout and analysis circuit 128.

In the illustrated embodiment, readout and analysis circuit 128 iselectrically coupled to detector array 110 by conductive traces 132positioned on the surface or in the interior of substrate 102, but inother embodiments controller 126 can be coupled to the elements by othermeans, such as optical means. Readout and analysis circuit 128 is alsocoupled to controller 126 and can send signals to, and receive signalsfrom, controller 126 so that the two elements can coordinate andoptimize operation of device 100. Although the illustrated embodimentshows controller 126 and readout and analysis circuit 128 as physicallyseparate units, in other embodiments the controller and the readout andanalysis circuit could be combined in a single unit.

In operation of device 100, the system is first powered up and anynecessary logic (i.e., software instructions) is loaded into controller126 and readout and analysis circuit 128 and initialized. Afterinitialization, the valve in filter and valve unit 104 is opened andpump 112 is set to allow flow through the fluid handling assembly. Fluidis then input to fluid handling assembly 101 through inlet 114 at acertain flow rate and/or for a certain amount of time; the amount oftime needed will usually be determined by the time needed forpre-concentrator 106 to generate adequate concentrations of theparticular chemicals whose presence and/or concentration are beingdetermined. As fluid is input to the system through inlet 114, it isfiltered by filter and valve assembly 104 and flows through elements104-112 within fluid handling assembly 101 by virtue of the fluidconnections between these elements. After flowing through elements104-112, the fluid exits the fluid handling assembly through exhaust124.

After the needed amount of fluid has been input through inlet 114, thevalve in filter and valve assembly 104 is closed to prevent furtherinput of fluid. After the valve is closed, a heater in pre-concentrator106 activates to heat the pre-concentrator. The heat releases thechemicals absorbed and concentrated by the pre-concentrator. As thechemicals are released from pre-concentrator 106, pump 112 is activatedto draw the released chemicals through gas chromatograph 108 anddetector array 110 and output the chemicals through exhaust 124.Activation of pump 112 also prevents backflow through fluid handlingassembly 101.

As the chemicals released from pre-concentrator 106 are drawn by pump112 through gas chromatograph 108, the chromatograph separates differentchemicals from each other in the time domain—that is, differentchemicals are output from the gas chromatograph at different times. Asthe different chemicals exit gas chromatograph 108 separated in time,each chemical enters MEMS detection array 110, where sensors in thedetection array detect the presence and/or concentration of eachchemical. The time-domain separation performed in gas chromatograph 108substantially enhances the accuracy and sensitivity of MEMS detectionarray 110, since it prevents numerous chemicals from entering thedetection array at the same time and thus prevents cross-contaminationand potential interference in the sensors within the array.

As individual sensors within MEMS detection array 110 interact with theentering time-domain-separated chemicals, the detection array senses theinteraction and outputs a signal to readout and analysis circuit 128,which can then use the signal to determine presence and/or concentrationof the chemicals. When readout and analysis circuit 128 has determinedthe presence and/or concentration of all the chemicals of interest itcan use various analysis techniques, such as correlation and patternmatching, to extract some meaning from the particular combination ofchemicals present and their concentrations.

FIG. 2A illustrates an embodiment of a MEMS pre-concentrator 200 thatcan be used as pre-concentrator 106 in device 100. Pre-concentrator 200includes a substrate 202 having a cover plate 204 bonded thereto andsealed around the perimeter of the substrate to create a cavity 206.Substrate 202 has formed therein an inlet 208 on one side, an outlet 210on a different side, and pockets 212 having absorbents therein. In oneembodiment, substrate 202 is a silicon substrate, but in otherembodiments substrate 202 can of course be made of other materials.Heater 216 is formed on the side of substrate 202 opposite the sidewhere cover plate 204 is attached.

In an embodiment where substrate 202 is silicon, inlet 208, outlet 210and pockets 212 can be formed using standard photolithographicpatterning and etching. Although the illustrated embodiment shows sevenpockets 212 a-212 g, the number of pockets needed depends on the numberof different chemicals to be absorbed and concentrated, and on thenature of the absorbents used. In an embodiment where each absorbentabsorbs only one chemical, the number of pockets 212 can correspondexactly to the number of chemicals to be absorbed and concentrated, butin other embodiments where each absorbent absorbs only one chemical agreater number of pockets can be used to increase the absorption area.In still other embodiments where each absorbent can absorb more than onechemical, a lesser number of pockets can be used.

Each pocket 212 has a corresponding absorbent 214 in its interior—pocket212 a has absorbent 214 a, pocket 212 b has absorbent 214 b, and so on.Although shown in the illustrated embodiment as a granular absorbent, inother embodiments absorbents 214 can be coatings on the walls of pockets212 or can be a continuous substance that partially or fully fills eachpocket 212. Other embodiments can include combinations of granular, wallcoatings or continuous filling absorbents. Each absorbent can have achemical affinity for one or more particular chemicals, meaning that theexact absorbents used will depend on the number and nature of chemicalsto be absorbed and concentrated. Examples of absorbents that can be usedinclude cabopack B, cabopack X, etc.

During operation of MEMS pre-concentrator 200 in device 100, fluid fromfilter and valve assembly 104 enters through inlet 208, passes throughabsorbent 214 a in pocket 212 a, and enters cavity 206. Cover plate 204helps guide fluid entering the cavity 206 into the different pockets 212b-212 g and through absorbents 214 b-214 g, until the fluid, minus thechemicals absorbed by absorbents 214 a-214 g, exits the pre-concentratorthrough outlet 210. Once enough fluid has flowed through thepre-concentrator, the valve in filter and valve assembly 104 is closedto prevent further flow through inlet 208. Heater 216 is then activated.Heater 216 heats absorbents 214 a-214 f, causing them to release theabsorbed chemicals through processes such as outgassing. Simultaneouslywith activating heater 216, or shortly thereafter, pump 112 isactivated, drawing the released chemicals out through outlet 210 to gaschromatograph 108.

FIG. 2B illustrates an alternative embodiment of a MEMS pre-concentrator250. MEMS pre-concentrator 250 is in many respects similar to MEMSpre-concentrator 200, The primary difference between the two is that inMEMS pre-concentrator 250, the cover plate 252 is directly bonded to thesubstrate 202 without formation of cavity 206 found in cover plate 204.In one embodiment of MEMS pre-concentrator 250, channels/openings 252can exist in substrate 202 between the different pockets 212 to allowthe fluid to flow through adjacent pockets. In operation of MEMSpre-concentrator 250, fluid enters through inlet 208, passes through thedifferent pockets 212 a-212 g via the channels/openings 252 between thepockets, and finally exits the pre-concentrator through outlet 210.

FIGS. 3A-3B illustrate embodiments of an individual MEMS gaschromatograph 300 that can be used as gas chromatograph 108 in device100. MEMS gas chromatograph 300 includes a substrate 302 with an inlet306 on one side, an outlet 308 on a different side, and a separationcolumn 310 having a stationary phase coating on its walls. A cover plate304 is bonded to substrate 302 to seal column 310. In one embodimentsubstrate 302 is a silicon substrate, but in other embodiments substrate302 can of course be made of other materials. In an embodiment wheresubstrate 302 is silicon, inlet 306, outlet 308 and column 310 can beformed using standard photolithographic patterning and etching, such asdeep reactive ion etching (DRIE). Temperature control 314 is formed onthe side of substrate 302 opposite the side where cover plate 204 isattached. In one embodiment, temperature control is integrated withchromatograph 300 and can include heating elements and/or coolingelements, or elements that are capable of both heating and cooling suchas a Peltier device. Temperature control 314 can also include one ormore temperature sensors 316 to allow for monitoring and/or feedbackcontrol of temperature control 314.

Channel or column 310 provides a continuous fluid path from inlet 306 tooutlet 308, and some or all of the walls of column 310 are coated with astationary phase coating that can interact with the chemicals beingseparated by the chromatograph or, in other words, the column walls arecoated with specific materials that have specific selectivity/separationpower for the desired gas analysis. How thoroughly and how fastchemicals are separated from the fluid depend on the stationary phasecoating, the overall path length of column 310, and the temperature. Fora given stationary phase coating, the longer the column the better thechemical spectrum separation, but a long column also extends theseparation time. For a given application, the required path length willtherefore usually be determined by a tradeoff among the coating, thecolumn length and the temperature. The illustrated embodiment showscolumn 310 as a spiral column in which the column path length willdepend on the number of coils in the spiral. In other embodiments,however, column 310 can be shaped differently. In one embodiment, column310 can be between 1 m and 10 m in length, but in other embodiment canbe outside this range. In the illustrated MEMS GC, column 310 can beformed by micromachining or micro-electro-mechanical-systems (MEMS)process on silicon wafer, glass wafer, PCB board, or any type ofsubstrate.

During operation of MEMS gas chromatograph 300 in device 100, fluid frompre-concentrator 106 enters through inlet 306 and passes through column310. As fluid passes through the column 310, the different chemicals inthe fluid interact with stationary phase coating 312 at different rates,meaning that the chemicals are separated after traveling through thecolumn, with the chemicals that interact strongly with the stationaryphase being separated first and the chemicals that interact weakly withthe stationary phase being separated last. In other words, chemicalsthat interact strongly with the stationary phase are retained longer inthe stationary phase, while chemicals that interacted weakly with thestationary phase retained less time in the stationary phase. In someembodiments of gas chromatograph 300 this time-domain separation canoccur according to molecular weight (e.g., chemicals with the lowestmolecular weight are separated first, followed by higher molecularweights), but in other embodiments it can occur according to otherchemical characteristics or other separation mechanisms. As thechemicals are time-domain separated, pump 112 draws them out of MEMS gaschromatograph 300 through outlet 308. Generally, the chemicals exitthrough outlet 308 in the reverse order of their separation—that is,chemicals with low retention time exit first, while chemicals withhigher retention times exit later. After leaving outlet 308, thechemicals enter detector array 110.

FIG. 3C illustrates an alternative embodiment of an individual gaschromatograph 350. Gas chromatograph 350 is in most respects similar togas chromatograph 300 shown in FIG. 3B. The primary difference betweengas chromatographs 300 and 350 is the configuration of the temperaturecontrol. In gas chromatograph 350, temperature control 352 is notintegrated into the chromatograph, but instead is an external component,such as a heating or cooling plate, that is thermally coupled to thechromatograph. Thermal coupling between external temperature control 352and the chromatograph can be accomplished, for example, using thermallyconductive adhesives or with thermal interface materials. As withtemperature control 314, temperature control 352 can include one or moretemperature sensors 354 to monitor the temperature and/or providefeedback control of the temperature control. Since the GC is small(about 1 inch range in one embodiment, but not limited to this range),faster heating and cooling control can be achieved with either theintegrated or external temperature controls.

FIGS. 3D and 3E together illustrate an alternative embodiment of anindividual gas chromatograph 380. The primary difference between gaschromatographs 380 and 350 is the formation in chromatograph 380 of aconventional chromatography column instead of a MEMS chromatographycolumn. Gas chromatograph 380 includes a substrate 382 having a cavityor opening 384 therein. Positioned within cavity 384 is a chromatographycolumn 386, which in one embodiment can be formed using coiled capillarytube used in conventional chromatography. A temperature control 386 isbonded to substrate 382 to close cavity 384, thus enclosing column 386.In one embodiment, temperature control 386 can be an externaltemperature control as shown in FIG. 3C, and can include one or moretemperature sensors 388 to monitor the temperature and/or providefeedback control of the temperature control. GC 380 can be packaged in asmall size to achieve faster heating and cooling control.

Operation of gas chromatograph 380 is similar to gas chromatograph 350shown in FIG. 3C. The primary difference between gas chromatographs 380and 350 is the formation of chromatography column. Instead of using MEMSfabricated column chip, the column can be formed by coiled capillarytube used in conventional chromatography. The column is then enclosed bya temperature control 381 as shown in FIG. 3D. Such GC can be packagedin a small size to achieve faster heating and cooling control.

FIGS. 4A-4B illustrate an embodiment of a detector array 400 that can beused as detector array 110 in device 100. Detector array 400 includes asubstrate 402 with an array of sensors S1-S9 formed thereon. In theillustrated embodiment sensors S1-S9 form a regularly shaped 3-by-3array of sensors, but in other embodiments the sensor array can have agreater or lesser number of sensors, and the sensors can be arranged inany pattern, regular or irregular.

A cover 404 is bonded to the perimeter of substrate 402 to form a cavity410 within which sensors S1-S9 are located. Cover 404 also includes aninlet 406 through which fluid can enter from gas chromatograph 108 andan outlet 408 through which fluid can exit to pump 112. A heater 412 isformed on the side of substrate 402 opposite the side where cover 404 isattached to control the temperature of detector array 400, and hence thesensors within the detector array, during operation. Although not shownin the figure, detector array 400 of course includes outputs by whichsignals generated by sensors S1-S9 can be output for processing.

Each sensor S1-S9 includes a surface with a coating thereon. Eachcoating used will have an affinity for one or more of the particularchemicals being detected, such that the coating absorbs or chemicallyinteracts with its corresponding chemical or chemicals. The interactionbetween coating and chemical in turn changes a physical property of thesensor such as resonant frequency, capacitance or electrical resistance,and that changed physical property of the sensor can be measured using atransducer or other measurement device. The particular coatings chosenfor sensors S1-S9 will depend on the chemicals that sensor array 110will be used to detect. The chemical affinity of coatings also variesstrongly with temperature, so that the operating temperature rangeshould be considered in selecting coatings. In an embodiment wheresensor array 110 will be used to detect volatile organic compounds inhuman breath—such as benzene, toluene, n-octane, ethylbenzene,m,p-xylene, α-pinene, d-limonene, nonanal, and benzaldehyde,2-methylhexane, 4-methyloctane, and so on—coatings that can be used indifferent applications include amorphous copolymers of2,2-bistrifluoromethyl-4,5-difluoro-1,3-dioxole (PDD) andtetrafluoroethylene (TFE), PtC12 (olefin), C8-MPN, etc.

Although the illustrated embodiment has nine sensors, the number ofsensors needed depends on the number of different chemicals to bedetected, and on the nature of the coatings used on the sensors. In anembodiment where each coating absorbs or chemically interacts with onlyone chemical the number of sensors can correspond exactly to the numberof chemicals to be detected, but in other embodiments it can bedesirable to have a given coating on more than one sensor forredundancy. In most cases, however, there is no one-to-one correlationbetween chemicals to coatings; in other words, each coating reacts withmore than one different chemical and the reaction between differentchemicals and a given coating will vary in nature and strength. Adetector array having sensors with different coatings is thereforeuseful because the response of the detector array can have differentpatterns for different gases.

In one embodiment of sensor array 400, sensors S1-S9 are MEMS sensorspositioned on the surface of substrate 402, meaning that they aresurface micromachined sensors. In other embodiments using MEMS sensors,however, sensors S1-S9 can be bulk micromachined sensors, meaning thatat least some of the MEMS sensors are formed within substrate 402instead of on the surface. Still other embodiments of sensor array 110using MEMS sensors can include combinations of surface-micromachined andbulk-micromachined sensors. Different types of MEMS sensors can be used,depending on the application and the required sensitivity. Examples ofMEMS sensors that can be used include chemiresistors, bulk acoustic wave(BAW) sensors, etc. In other embodiments of detector array 400, one ormore of sensors S1-S9 can be a non-MEMS sensor. Examples of non-MEMSsensors that can be used in detector array 400 include quartz crystalmicrobalance (QCM) or surface acoustic wave (SAW) sensors with quartz orGallium Arsenide (GaAs) substrates.

During operation of MEMS detector array 400 in device 100, fluid fromgas chromatograph 108 enters through inlet 406 and passes into cavity410. Fluid entering cavity 410 carries time-domain separated chemicals.As each chemical enters cavity 410 it interacts with one or more sensorswhose coating has an affinity for that chemical. The interaction of thechemical with the sensor is sensed and measured, and the presence andconcentration of the particular chemical can be extracted. As more fluidflows into cavity 410, the first chemical is pushed out of cavity 410through outlet 408 and fluid with the next time-domain-separatedchemical enters cavity 410, interacts with the sensor array and ismeasured. This process continues until all the time-domain-separatedchemicals from gas chromatograph 108 have flowed through detector array110. In some embodiments where the affinity of the coatings for theirchemicals is not strong, detector array 110 can be re-usable: after alltime-domain-separated chemicals have been sensed, heater 412 can beactivated to heat the sensors and cause the coatings to release therespective chemicals with which they interacted, making the interactionreversible. In embodiments where the affinity of each coating for itschemicals could be strong, heating of the sensor array could helprelease the partially absorbed gas from the coating materials.

FIG. 5 illustrates an embodiment of a system 500 using an alternativeembodiment of a MEMS-based gas analysis device 502. Device 502 is inmost respects similar to device 100. The primary difference betweendevice 502 and device 100 is the presence in device 502 of a wirelesstransceiver circuit 504 and an antenna 506 mounted on substrate 102.Wireless transceiver circuit 504 can both transmit (Tx) data and receive(Rx) data and is coupled to reading and analysis circuit 128 and antenna506.

In one embodiment of system 500, transceiver 504 can be used towirelessly transmit raw data from reading and analysis circuit 128 toone or both of a router 508 and a computer 510. When transmitted torouter 508, the data can then be re-transmitted to another destinationfor analysis. For example, in an application where device 502 is usedfor health-related chemical analysis, data sent to router 508 can bere-transmitted to one or more of a doctor's office, a hospital, agovernment health department, or someplace else for analysis andinterpretation. After analysis is complete, or if there is a problemwith the data, the doctor's office, hospital or health department cansend instructions to device 502 through router 508, antenna 506 andtransceiver 504 to signal the result, to try to fix or improve the data,or to signal that the test must be performed again.

Continuing with the same health-care example, in the same or anotherembodiment of system 500, wireless transceiver 504 can be used totransmit raw data to computer 510. Computer 510 can either forward theraw data to a doctor, hospital, etc., as did the router, or can analyzethe data with software installed thereon to provide extract informationfrom the data, such as one or more possible medical diagnoses, andprovide the extracted information to the user of device 502. When itprovides analysis and medical diagnoses, computer 510 can also forwardthe diagnosis, alone or with the analysis and raw data, on to thedoctor, hospital, etc. As with the router, the doctor's office, hospitalor health department can send instructions to device 502 throughcomputer 510, antenna 506 and transceiver 504 to try to fix or improvethe data, to signal that the test must be performed again, and so on.

Again continuing with the same health-care example, in still anotherembodiment of system 500 the raw data can be processed, and informationsuch as potential diagnoses extracted from the data, by reading andanalysis circuit 128. The potential diagnoses determined by reading andanalysis circuit 128 can then be sent to computer 510 to be reviewed bythe user and/or forwarded, or can be immediately forwarded alone or withthe supporting raw data to the doctor's office, etc.

FIG. 6 illustrates an embodiment of a system 600 using an alternativeembodiment of a MEMS-based gas analysis device 602. Device 602 is inmost respects similar to device 502. The primary difference betweendevice 502 and device 602 is that the wireless transceiver circuit 504and antenna 506 are replaced with a hardware data interface 604 coupledto reading and analysis circuit 128. In one embodiment, hardware datainterface 604 could be a network interface card, but in otherembodiments hardware data interface can be an Ethernet card, a simplecable plug, etc. External devices can be connected to device 602 throughtraditional means such as cables. Although it has a differentcommunication interface, device 602 and system 600 have all the samefunctionality as device 502 and system 500. As with system 500, insystem 600 MEMS-based gas analysis device 602 can transmit data to, andreceive data from, one or both of a computer 608 and a wireless device606, such as a cell phone or personal digital assistant (PDA). Whentransmitted to wireless device 606 the data can then be forwarded to adoctor's office, hospital, or government health department, and therecipients of the data can in turn send data or instructions back to gasanalysis device 602 through the wireless device. As in system 500, whendata is transmitted to computer 608 it can be forwarded or can beanalyzed by the computer and the result displayed for the user and/orforwarded, and instructions can be transmitted to device 602 throughcomputer 608. Similarly, the data from gas analysis device 602 can beanalyzed by reading and analysis circuit 128. After analysis by circuit128, the extracted information (e.g., one or more diagnoses) and/or theraw data can be forwarded via the hardware data interface 604.

FIG. 7 illustrates an alternative embodiment of a MEMS-based gasanalysis device 700. Device 700 is in most respects similar to device100. The primary difference between system 700 and device 100 is thatdevice 700 includes an on-board display 702 for conveying to a user theresults of the analysis performed by reading and analysis circuit 128.

The illustrated embodiment uses an on-board text display 702, forexample an LCD screen that can convey text information to a user. Forexample, in a health care example display 702 could be used to displaythe test results in analog numbers indicating the situation of patients.Display 702 could indicate a positive or negative diagnosis, couldindicate probabilities of a given diagnosis, or could indicate the rawdata from the detector array. In another health care embodiment, simplerdisplays can be used, such as one with three lights that indicate apositive, negative, or indeterminate result depending on which light isswitched on.

FIG. 8 illustrates an alternative embodiment of a MEMS-based gasanalysis device 800. Device 800 is in most respects similar to device100. The primary difference between device 800 and device 100 is that indevice 800 one or more elements of fluid handling assembly 101 arereplaceable. In the illustrated embodiment, the elements are madereplaceable by mounting them onto substrate 102 using sockets: filterand valve assembly 104 is mounted to substrate 102 by socket 804,pre-concentrator is mounted to substrate 102 by socket 804, gaschromatograph 108 is mounted to substrate 102 by socket 808, detectorarray 110 is mounted to substrate 102 by socket 810, and pump 112 ismounted to substrate 102 by socket 812. In one embodiment, sockets804-812 are sockets such as zero insertion force (ZIF) sockets thatpermit easy replacement by a user, but in other embodiments other typesof sockets can be used. Although the illustrated embodiment shows allthe components of fluid handling assembly 101 being replaceable, inother embodiments only some of the components such as pump 112 anddetector array 110 can be made replaceable.

FIG. 9 illustrates an alternative embodiment of a MEMS-based gasanalysis device 900. Gas analysis device 900 is in most respects similarto device 100. The primary difference between device 900 and device 100is that device 900 includes provisions for an external pre-concentrator902 (i.e., a pre-concentrator not mounted on substrate 102). In theembodiment shown, a valve 904 is placed between pre-concentrator 106 andgas chromatograph 108, and provisions are made to attach externalpre-concentrator 902 to the valve. Valve 904 allows the user to useexternal pre-concentrator 902 instead of, or in addition to, on-boardpre-concentrator 106. In one embodiment external pre-concentrator 902 isa breath collection bag, but in other embodiments it can be somethingdifferent. In an alternative embodiment of device 900 (not shown),pre-concentrator 106 can be permanently removed and replaced by externalpre-concentrator 902. In another embodiment where externalpre-concentrator 902 replaces pre-concentrator 106, instead of insertinga valve between pre-concentrator 106 and gas chromatograph 108, externalpre-concentrator 902 can be coupled upstream of the filter and valveassembly 104.

FIGS. 10A-10F illustrate embodiments of cascaded gas chromatographs(CGCs) that can be used, for example, as gas chromatograph 108 in gasanalysis system 100. As explained previously, GC column coatings areusually optimized for specific temperatures and chemicals, so that nosingle GC can separate a large array of chemicals, even by varying itstemperature. Cascading multiple GCs with individual temperature controlcan provide complementary gas separation between GCs, resulting inbetter overall separation and a better, more defined chemical spectrum.

FIG. 10A illustrates a cascaded gas chromatograph (CGC) 1000 thatincludes a first gas chromatograph (GC) 1002 coupled to a second GC1008. In the illustrated embodiment, GCs 1002 and 1008 are coupled inseries such that outlet 1006 of GC 1002 is coupled to inlet 1010 of GC1008 by a fluid connection 1014. Outlet 1012 of GC 1008 is coupled to adetector 1018 by a fluid connection 1016, although in other embodimentsoutlet 1012 could be coupled to some entirely difference component.Although the embodiment illustrated in the figure has only two GCs, inother embodiments one or more additional GCs, as well as othercomponents such as additional fluid connections, flow splitters,three-way valves detectors and switch valves, can be added to form alarger cascade of GCs.

In some embodiments, GCs 1002 and 1008 can have the samecharacteristics, but in other embodiments GCs 1002 and 1008 need nothave the same characteristics and can have different column lengths,column coatings, operating temperatures, etc. In one embodiment, forexample, GC 1002 can be coated with material A, which can be especiallyselective to polar or non-polar chemicals, and can have its optimumtemperature control profile to separate specific chemicals. Meanwhile,GC 1008 can have a different column length and can be coated withanother material B, which can separate different chemicals that GC 1002cannot resolve (separate); in other words, GC 1008 is complementary toGC 1002. Since each GC in the configuration can has its own temperaturecontrol, GC 1008 can be optimized to separate the remaining gases ofinterest that are not resolved (separated) by GC 1002. The separatedgases can then be detected by detector 1018 at output of GC 1008.

In the illustrated embodiment, GCs 1002 and 1008 are MEMS gaschromatographs with individual temperature controls, such as those shownin FIG. 3B or 3C, but in other embodiments they can be traditional GCswith individual and independent temperature controls, such as thecapillary column chromatographs shown in FIGS. 3D-3E and 12A-12C. Theindividual temperature controls allow the operating temperature of eachGC to be controlled independently of the other. In other embodiments GCs1002 and 1008 need not be of the same type—that is, CGC 1000 can includeboth MEMS and non-MEMS chromatographs. In some embodiments bothchromatographs can have the same kind of temperature control, but inother embodiments both chromatographs need not have the same temperaturecontrol; for example, in the illustrated embodiment with two MEMSchromatographs, GC 1002 can have an integrated temperature control asshown in FIG. 3B, while GC 1008 has an external temperature control, asshown in FIGS. 3C-3E. In one embodiment, detector 1018 is a detectorarray as shown in FIGS. 4A-4B, but in other embodiments it can be adifferent type of detector.

In operation of CGC 1000, a carrier fluid having one or more chemicalstherein enters GC 1002 through inlet 1004 and flows through the GC'scolumn. The GC's temperature control is used to establish and/ormaintain the temperature of GC 1002 at the temperature needed for thedesired separation of the chemicals from the fluid. The carrier fluid,with any chemicals not resolved (separated) by GC 2002, exits throughoutlet 1006 into fluid connection 1014. Fluid connection 1014 carriesthe fluid into GC 1008, where the fluid flows through the GC's columnand some or all of the unresolved chemicals remaining after GC 1002 areseparated. As with GC 1002, the temperature control of GC 1008 is usedto establish and/or maintain the temperature needed for the desiredseparation of the chemicals from the fluid. Outlet 1012 of GC 1008 iscoupled to a detector, which can then be used to detect the chemicalsseparated from the carrier fluid by the two GCs. In another embodimentof the operation of GC 1000, each individual GC's temperature does notneed to be fixed at certain temperature. Each GC can be controlled tohave different dynamic temperature ramping profile to achieve desirechemical separation.

FIG. 10B illustrates an alternative embodiment of a CGC 1025. CGC 1025is in most respects similar to CGC 1000. The primary difference betweenthe two is the presence in CGC 1025 of a pre-concentrator and/or trap(PC/T) 1027 coupled into the fluid connection 1014. In one embodiment,PC/T 1027 can be a chip or other MEMS-scale device through which fluidflows when traveling in fluid connection 1014 from outlet 1006 to inlet1010, but in other embodiments it can be a non-MEMS device. CGC 1025operates similarly to CGC 1000, but in GC 1025 PC/T 1027 can beperiodically cooled and/or heated to trap and release separatedchemicals with higher concentration and short spectrum before they enterGC 1008. GC 1008 can then further separate the chemicals as describedfor CGC 1000 above. With the addition of PC/T 1027, the gases spectrumcan be narrower with higher gas concentration for the detector sensing.

FIG. 10C illustrates an alternative embodiment of a CGC 1050 withmultiple flow paths. CGC 1050 is similar to CGC 1000 in that GCs 1002and 1008 are coupled such that outlet 1006 of GC 1002 is coupled toinlet 1010 of GC 1008 by a fluid connection 1014. Outlet 1012 of GC 1008is coupled to a detector 1018 by a fluid connection 1016, and detector1018 is further coupled to a switch valve 1052 by a further fluidconnection. In CGC 1050, an additional fluid connection 1056 is coupledto fluid connection 1014 by a flow splitter or three-way valve 1054. Inaddition to being coupled to fluid connection 1014, fluid connection1056 is coupled to the inlet of detector 1058, and a switch valve 1060is fluidly coupled to the outlet of detector 1058. Switch valves 1018and 1058 can control whether gases can flow to the correspondingdetectors for gas sensing. Detectors 1018 and 1058 can be different andhave specific sensitivity to different gases. Although the embodimentillustrated in the figure has only two GCs, in other embodiments one ormore additional GCs, as well as other components such as additionalfluid connections, flow splitters, three-way valves detectors and switchvalves, can be added to form a cascaded array of GCs.

CGC 1050 has different modes of operation, depending on whether element1054 is a flow splitter or a three-way valve. In an embodiment whereelement 1054 is a flow splitter, a carrier fluid having one or morechemicals therein enters GC 1002 through inlet 1004 and flows throughthe GC's column. The GC's temperature control is used to establishand/or maintain the temperature of GC 1002 at the temperature needed forthe desired separation of the chemicals from the fluid. The carrierfluid, with any chemicals not resolved (separated) by GC 1002, exitsthrough outlet 1006 into fluid connection 1014. A portion of the fluidcarried by fluid connection 1014 is directed into GC 1008, and a portionof the fluid is directed into fluid connection 1056. The portionentering GC 1008 flows through the GC's column and some or all of theunresolved chemicals remaining after GC 1002 are separated. As with GC1002, the temperature control of GC 1008 is used to establish and/ormaintain the temperature needed for the desired separation of thechemicals from the fluid. Outlet 1012 of GC 1008 is coupled to detector,which can then be used to detect the chemicals separated from thecarrier fluid by the two GCs. The portion of fluid directed into fluidconnection 1056 flows to detector 1058. When both switch valves 1052 and1060 are opened, partial gases that are separated by GC 1002 can bedirectly sensed by detector 1058, while partial gases are fed into GC1008 for further separation and sensing by detector 1018. In anothermode of operation where element 1054 is a flow splitter, only one ofswitch valves 1052 and 1060 is opened. With only one switch valve open,full gas can flow path can be switched between detectors 1018 and 1058without losing partial gases (lower gases amount to be sensed). In anembodiment in which element 1054 is a three-way valve, the three-wayvalve can be used to control the flow and switch valves 1052 and 1060can be eliminated.

FIG. 10D illustrates an alternative embodiment of a CGC 1051. CGC 1051is in most respects similar to CGC 1050. The principal differencebetween the two is the omission of detector 1058 from CGC 1051. Foroperations in which some chemical gases exiting from GC 1002 are notneeded, CGC 1051 can be used to remove the unwanted chemicals byswitching or directing the chemicals exiting GC 1002 into fluidconnection 1056 and discarding them.

FIG. 10E illustrates an alternative embodiment of a CGC 1075. CGC 1075is in most respects similar to CGC 1050. The primary difference betweenthe two is the presence in CGC 1075 of pre-concentrator and/or trap(PC/T) 1079 coupled to fluid connection 1014 and pre-concentrator and/ortrap (PC/T) 1077 coupled to fluid connection 1056. In one embodiment,PC/Ts 1077 and 1079 can be pre-concentrator and/or trap chips or otherMEMS-scale device through which fluid flows when traveling through fluidconnections 1014 and 1056, but in other embodiments PC/Ts 1077 and 1079need not be MEMS-scale devices. In still other embodiments, PC/Ts 1077and 1079 can be different types of pre-concentrators or traps. CGC 1075operates in a manner similar to CGC 1050, except that PC/Ts 1077 and1079 are used to periodically trap/release narrow and higherconcentration gas spectrums for detector sensing.

FIG. 10F illustrates an alternative embodiment of a CGC 1090. CGC 1090is similar in most respects to CGC 1075. The primary difference betweenCGC 1090 and CGC 1075 is the addition in CGC 1090 of a fluid connection1097 between the outlet of GC 1008 and the inlet of GC 1002. Apre-concentrator and/or trap (PC/T) 1181 and switch valve 1099 arecoupled in fluid connection 1097. Fluid connection 1097 allows gases tore-circulate between two or more GCs to increase the effective GC columnlength without having to physically lengthen the GC column or addadditional GCs in series. An additional switch valve 1187 is alsocoupled to fluid connection 1010 between the outlet of GC 1002 and theinlet of GC 1008. In the illustrated embodiment, PC/T 1077 (see FIG.10E) has been removed from fluid connection 1026, but in otherembodiments of CGC 1090 it could be reinserted. Although the embodimentillustrated in the figure has only two GCs, in other embodiments one ormore additional GCs or detectors, as well as other components such asadditional fluid connections, flow splitters, three-way valves detectorsand switch valves, can be added to form a cascaded array of GCs, asindicated by dots 1091.

CGC 1090 includes different modes of operation, depending on how fluidis routed through the CGC. The fluid routing is controlled by switchvalves 1030, 1034, 1099, 1183 and 1187. In one mode, switch valve 1099and switch valve 1034 (for detector 1032) are closed, the gases flowtowards detector 1028 with switch valve 1030 open. The flowconfiguration is similar to FIG. 10A when there is no PC/T used orsimilar to configuration shown in FIG. 10B when a PC/T is used.

In another operating mode of CGC 1090, when the micro switch valve 1099and switch valve 1034 are open while switch valves 1183 and 1187 areclosed, the gases that flow through GC 1008 can be re-circulated back toGC 1002 inlet and pass though GC 1002 again for further gas separationand is then sensed by detector 1032. PC/T 1185 can be included in theflow path between GCs as an option to produce narrower gas spectrum.

FIG. 11A illustrates another alternative embodiment of a CGC 1100. CGC1100 includes GCs 1102, 1108 and 1116. In the illustrated embodiment,GCs 1102 and 1108 are coupled such that outlet 1106 is coupled to inlet1112 by a fluid connection 1110. Outlet 1114 of GC 1008 is coupled to aninlet of detector 1128, while a switch valve 1130 is coupled to theoutlet of detector 1128. An additional fluid connection 1126 is coupledto fluid connection 1110 by a flow splitter or three-way valve 1124.Fluid connection 1126 is also coupled to inlet 1118 of GC 1116, whileoutlet 1120 of GC 1118 is coupled to an inlet of detector 1132. A switchvalve 1130 is coupled to the outlet of detector 1132. Although theembodiment illustrated in the figure has only three GCs, in otherembodiments one or more additional GCs, as well as other components suchas additional fluid connections, flow splitters, three-way valvesdetectors and switch valves, can be added to form a cascaded array ofGCs, as indicated by dots 1136.

The exact characteristics of each GC in CGC 1100, such as column length,column coatings and operating temperature, will usually depend onoperational considerations such as the anticipated uses of CGC 1100,what chemicals the CGC will be used to separate, and so on. In someembodiments, GCs 1102, 1108 and 1116 can have the same characteristics,but in other embodiments GCs 1102, 1108 and 1116 need not have the samecharacteristics and can have different column lengths, column coatings,operating temperatures, etc. In one embodiment, for example, GC 1002 canbe coated with material A, which can be especially selective to polar ornon-polar chemicals, and can have its optimum temperature controlprofile to separate specific chemicals. Meanwhile, GCs 1108 and 1116 canhave different column lengths and can be coated with other materials Band C which can separate chemicals that GC 1002 cannot resolve(separate); in other words, GCs 1108 and 1116 are complementary to GC1002. Since each GC can has its own temperatures control, GCs 1108 and1116 can be optimized to separate the remaining chemicals of interestthat are not resolved (separated) by GC 1002. The separated chemicalscan then be detected by detector 1128 at the output of GC 1108 anddetector 1132 at the outlet of GC 1116.

In the illustrated embodiment, GCs 1102, 1108 and 1116 are MEMS gaschromatographs with individual temperature controls, such as those shownin FIG. 3B or 3C, but in other embodiments they can be traditional GCswith individual temperature controls, such as FIG. 3D and the capillarycolumn chromatographs shown in FIGS. 12A-12C. The individual temperaturecontrols allow the temperature of each GC to be controlled independentlyof the other. In other embodiments GCs 1102, 1108 and 1116 need not beof the same type—that is, CGC 1100 can include both MEMS and non-MEMSchromatographs, can include GCs with different column coatings,different temperature responses, different column configurations, and soforth. In some embodiments all chromatographs can have the same kind oftemperature control, but in other embodiments GCs 1102, 1108 and 1116need not have the same temperature controls; for instance, in theillustrated embodiment with MEMS chromatographs, GCs 1102 and 1108 canhave an integrated temperature control as shown in FIG. 3B, while GC1116 can have an external temperature control, as shown in FIG. 3C.

CGC 1100 includes different modes of operation depending on how fluid isrouted through the CGC. In an embodiment in which element 1124 is a flowsplitter, the fluid routing is controlled by the operation of switchvalves 1130 and 1134. A carrier fluid having one or more chemicalstherein enters GC 1102 through inlet 1104 and flows through the GC'scolumn. The GC's temperature control is used to establish and/ormaintain the temperature of GC 1102 at the temperature needed for thedesired separation of the chemicals from the fluid. The carrier fluid,with any chemicals not resolved (separated) by GC 1102, exits throughoutlet 1106 into fluid connection 1110.

After exiting GC 1102, a portion of the fluid carried by fluidconnection 1110 is directed into GC 1108, and a portion of the fluid isdirected into GC 1116 through fluid connection 1126. The portionentering GC 1108 flows through the GC's column and some or all of theunresolved chemicals remaining after GC 1102 are separated. As with GC1102, the temperature control of GC 1108 is used to establish and/ormaintain the temperature needed for the desired separation of thechemicals from the fluid. Outlet 1114 of GC 1108 is coupled to adetector 1128, which can then be used to detect the chemicals separatedfrom the carrier fluid by the two GCs. The portion of fluid entering GC1116 flows through the GC's column and some or all of the unresolvedchemicals remaining after GC 1102 are separated. As with GC 1102, thetemperature control of GC 1116 can be used to establish and/or maintainthe temperature needed for the desired separation of the chemicals fromthe fluid. Outlet 1120 of GC 1116 is coupled to detector 1132, which canthen be used to detect the chemicals separated from the carrier fluid bythe two GCs.

When both switch valves 1130 and 1134 are opened, carrier fluid withchemicals not separated by GC 1102 can be input to GCs 1108 and 1116 forfurther separation, after which the separated chemicals can be sensed bydetectors 1128 and 1132. In an alternative mode of operation whereelement 1124 is a flow splitter, only one of switch valves 1130 and 1134can be opened. In such a case, the flow path can be switched between GCs1108 and 1116 without losing partial gases (lower gases amount to besensed). In an embodiment in which element 1124 is a three-way valve,the three-way valve can be used to control the flow between GCs 1108 and1116, and switch valves 1128 and 1132 can be eliminated. By combiningthe output spectrums from all the detectors, the resulting cascadedmicro-GC connection array can produce multi-dimensional gas spectrums,which can significantly boost the gas selectivity and separation powerof such system.

FIG. 11B illustrates an alternative embodiment of a CGC 1150. CGC 1150is in most respects similar to CGC 1100. The primary difference betweenthe two is the presence in CGC 1150 of a pre-concentrators and/or traps(PC/T) in fluid connections 1110 and 1126 to periodically trap/releasenarrow and higher concentration gas spectrums for detector sensing. CGC1150 operates in a manner similar to CGC 1110, except that PC/Ts 1152and 1154 are used to periodically trap/release narrow and higherconcentration gas spectrums for detector sensing.

FIG. 11C illustrates an alternative embodiment of a CGC 1175. CGC 1175is in most respects similar to CGCs 1100 and 1150. The primarydifference in CGC 1175 is that outlet 1114 of GC 1108 and outlet 1120 ofGC 1116 are coupled to a common outlet 1176 by element 1178. A commonoutlet is one that is shared by two or more other individual outlets; inother words, a common outlet is one into which at least two individualother outlets can direct their flow. In one embodiment, element 1178 canbe one or more valves, but in other embodiments it can be anotherelement such as one or more flow diverters, or in still otherembodiments can be some combination of one or more valves with one ormore flow diverters. A detector 1180 and switch valve 1182 can also becoupled to common outlet 1176.

In some embodiments of CGC 1175 the flow from the individual outlets canbe directed into the common outlet simultaneously, but in otherembodiments the flow from individual outlets into the common outlet neednot be simultaneous. In an embodiment of CGC 1175 where element 1178 isa flow splitter, CGC 1175 operates similarly to CGCs 1110 and 1150,except that the flow from both GCs 1108 and 1116 is simultaneouslyrouted into detector 1180. In an embodiment of CGC 1175 where element1178 includes one or more valves, the valve or valves can be used toswitch between the outlet of GC 1108 and the outlet of GC 1116, so thatat any given time detector 1180 receives flow from only one of GCs 1108and 1116. As with CGCs 1100 and 1150, in other embodiments one or moreadditional GCs, as well as other components such as additional fluidconnections, flow splitters, three-way valves detectors and switchvalves, can be added to form a cascaded array of GCs, as indicated bydots 1136. In such embodiments, groups of two or more GCs can be coupledto one or more common outlets, so that there need not be a one-to-onecorrespondence between the number of detectors and the number of GCs.

FIGS. 12A-12C illustrate alternative embodiments of cascaded gaschromatographs (CGCs) using non-MEMS chromatographs, such as capillarycolumn (or capillary channel) chromatographs. FIG. 12A illustrates acascaded gas chromatograph (CGC) 1200 that includes a first gaschromatograph (GC) 1202 coupled to a second GC 1204. In the illustratedembodiment, GCs 1202 and 1204 are capillary column gas chromatographscoupled in series, such that outlet of GC 1202 is coupled to an inlet ofGC 1204 by a fluid connection 1208. Outlet 1210 of GC 1008 can becoupled to another component such as a detector, for example as shown inFIG. 10A.

In the illustrated embodiment, GCs 1202 and 1204 are kept in separatetemperature zones, each with its own individual temperature controls: GC1202 is in temperature zone 1212, while GC 1204 is in temperature zone1214. Temperature zone 1212 can be controlled independently oftemperature zone 1214, so that the temperatures of the GCs can becontrolled independently. In one embodiment, temperature zones 1212 and1214 can be individually controllable ovens or autoclaves, while inother embodiments temperature zones 1212 and 1214 can be individuallycontrollable refrigeration units. In another embodiment, the temperaturezones can be individual thermally-insulated temperature substrate orenclosure as shown in FIG. 3D. In other embodiments, temperature zones1212 and 1214 need not be the same type; for instance, in one embodimenttemperature zone 1212 can be an oven while temperature zone 1214 can bea refrigeration unit. In still other embodiments, at least one oftemperature zones 1212 and 1214 can be capable of both heating andcooling.

In operation of CGC 1200, a carrier fluid having one or more chemicalstherein enters GC 1202 through inlet 1206 and flows through the GC'scolumn. Temperature zone 1212 is used to establish and/or maintain thetemperature of GC 1202 at the temperature needed for the desiredseparation of the chemicals from the fluid. The carrier fluid, with anychemicals not resolved (separated) by GC 1202, exits into fluidconnection 1208. Fluid connection 1208 carries the fluid into GC 1204,where the fluid flows through the GC's column and some or all of theunresolved chemicals remaining after GC 1202 are separated. As with GC1002, temperature zone 1214 is used to establish and/or maintain thetemperature needed for the desired separation of chemicals from thefluid in GC 1204. Outlet 1210 of GC 1204 can be coupled to a detector,which can then be used to detect the chemicals separated from thecarrier fluid by the two GCs.

FIG. 12B illustrates an alternative embodiment of a CGC 1250. CGC 1250is in most respects similar to CGC 1200. In CGC 1250, GC 1202 is withintemperature zone 1252, while GC 1204 is within temperature zone 1254.The primary difference between CGC 1200 and CGC 1250 is theconfiguration of the temperature zones: in the illustrated embodiment,temperature zone 1252 is within temperature zone 1254. In oneembodiment, temperature zone 1254 can be an oven or autoclave whiletemperature zone 1252 is a sub-oven within temperature zone 1252, butthermally insulated from temperature zone 1252 and independentlycontrollable from temperature zone 1252. In another embodimenttemperature zone 1254 can be a refrigeration unit while temperature zone1252 is a sub-unit within temperature zone 1252, but thermally insulatedfrom temperature zone 1252 and independently controllable fromtemperature zone 1252. CGC 1250 operates similarly to GC 1200.

FIG. 12C illustrates an alternative embodiment of a CGC 1275. In theillustrated embodiment, GCs 1202, 1204 and 1280 are capillary column GCscoupled such that outlet of GC 1202 is coupled to inlet of GC 1204 by afluid connection 1208. An additional fluid connection 1278 is coupled tofluid connection 1208 by a flow splitter or three-way valve 1276. Fluidconnection 1278 is also coupled to the inlet of GC 1280. Outlet 1210 ofGC 1204 and outlet 1282 of GC 1280 can be coupled to additionalcomponents such as detectors.

In the illustrated embodiment, GCs 1202, 1204 and 1280 are kept inseparate temperature zones, each with its own independent temperaturecontrols: GC 1202 is in temperature zone 1252, GC 1204 is in temperaturezone 1254, and GC 1280 is in temperature zone 1284. In one embodiment,temperature zones 1252, 1254 and 1284 can be individually andindependently controllable ovens or autoclaves, while in otherembodiments temperature zones 1252, 1254 and 1284 can be independentlycontrollable refrigeration units. In other embodiments, temperaturezones 1252, 1254 and 1284 need not be the same type; for instance, inone embodiment temperature zone 1252 could be an oven while temperaturezones 1254 and 1284 can be refrigeration units. In another embodiment,temperature zone 1254 can be an oven in which temperature zones 1252 and1284 can be individual thermally-isolated temperature substrate orenclosure as shown in FIG. 3D. In still other embodiments, at least oneof temperature zones 1212 and 1214 can be capable of both heating andcooling. Although the embodiment illustrated in the figure has onlythree GCs, in other embodiments one or more additional GCs andadditional temperature zones, as well as other components such asadditional fluid connections, flow splitter, three-way valves, detectorsand switch valves, can be added to form a cascaded array of GCs.

CGC 1275 includes different modes of operation depending on how fluid isrouted through the CGC. In an embodiment in which element 1276 is a flowsplitter, the fluid routing is controlled by the operation of switchvalves coupled to outlets 1210 and 1282. When both switch valves areopened, carrier fluid with chemicals not separated by GC 1202 can beinput to GCs 1204 and 1280 for further separation, after which theseparated chemicals can be sensed by detectors coupled to the outlets.In an alternative mode of operation where element 1276 is a flowsplitter, only one of the switch valves can be opened. In such a case,the flow path can be switched between GCs 1204 and 1280 without losingpartial gases (lower gases amount to be sensed). In an embodiment inwhich element 1276 is a three-way valve, the three-way valve can be usedto control the flow between GCs 1204 and 1280, and switch valves can beeliminated.

DEVICE APPLICATIONS

Pre-clinical studies on human breath analysis have found that certainvolatile organic compounds (VOCs) of exhaled human breath are correlatedto certain diseases, such as pneumonia, pulmonary tuberculosis (TB),asthma, lung cancer, liver diseases, kidney diseases, etc. Thecorrelations are especially evidential for lung-related diseases.Current analytical systems still rely on large and expensive laboratoryinstruments, such as gas chromatography (GC) and mass spectrometry (MS).Mass spectrometers in particular are impossible to miniaturize, makingwidespread use of these diagnostic instruments impossible.

The embodiments of MEMS-based gas analysis sensors discussed aboveprovide a solution to this problem, and in particular could be usedadvantageously to diagnose and monitor various diseases such as asthma,lung cancer, lung-related diseases, and other non-lung diseases such askidney and liver diseases, and etc.

Asthma

Asthma is a chronic disease; therefore, regularly monitoring patient'sstatus is helpful to doctor on tracking patient's healing progresses.Therefore, the new idea of handheld diagnostics would make the breathanalysis possible done at home or anywhere. In current diagnostics thebasic measurement is peak flow rate and the following diagnosticcriteria are used by the British Thoracic Society, but the peak flowrate is a physical quantity measurement. Breath analysis could providespecific root causes of the bronchi contraction by measuring the VOCsfrom patient's breath. Embodiments of the MEMS-based gas analysissystems could be used to monitor the efficacy of the medication.Furthermore, the medication therapy can be tailored to individualpatient through this active monitoring by using this home-based device.

Tuberculosis

One third of the world's current population has been infected by TB. And75% of the cases are pulmonary TB. The infected rate in the developingcountries is much higher than developed countries. Therefore, there areurgent needs of developing affordable diagnostic devices for developingcountries. Embodiments of the MEMS-based gas analysis system wouldprovide a cost-effective solution. Tuberculosis is caused byMycobacterium. Current diagnostic is time consuming and difficult sinceculturing the slow growing Mycobacterium takes about 6 weeks. Therefore,a complete medical evaluation, including chest X-ray, Tuberculosisradiology, tuberculin skin test, microbiological smears and cultures, isused to get more accurate assessment. Therefore, the rapid diagnostic isvery valuable and our breath analysis approach could achieve such needs.

Lung Cancer

With early detection and treatment, the 5-year survival rate for lungcancer improves dramatically. Current diagnostic methods, such as chestX-ray and CT (computed tomography) scan, are difficult to detect earlystage lung cancer. Breath analysis using embodiments of the MEMS-basedgas analysis system could diagnose the early stage lung cancer.

Classification of Lung-Related Diseases with Similar Symptoms

Breath analysis on exhaled VOCs is viable method to identify patient'slung-related diseases, which has similar symptoms. For example,embodiments of the MEMS-based gas analysis system can provide the testeddata to medical doctors to classify which disease between cool,lung-cancer, or pneumonia the patient would have. Breath analysis wouldbe the first screening test because of its simplicity before going formore tedious diagnostic measurements.

The above description of illustrated embodiments of the invention,including what is described in the abstract, is not intended to beexhaustive or to limit the invention to the precise forms disclosed.While specific embodiments of, and examples for, the invention aredescribed herein for illustrative purposes, various equivalentmodifications are possible within the scope of the invention, as thoseskilled in the relevant art will recognize. These modifications can bemade to the invention in light of the above detailed description.

The terms used in the following claims should not be construed to limitthe invention to the specific embodiments disclosed in the specificationand the claims. Rather, the scope of the invention is to be determinedentirely by the following claims, which are to be construed inaccordance with established doctrines of claim interpretation.

The invention claimed is:
 1. A cascaded gas chromatograph comprising: a first gas chromatograph including a separation column formed in or on a first substrate and a first thermoelectric cooler thermally coupled to the first substrate, wherein the first thermoelectric cooler can both heat and cool the separation column of the first gas chromatograph; a second gas chromatograph including a separation column formed in or on a second substrate and a second thermoelectric cooler thermally coupled to the second substrate, wherein the second thermoelectric cooler can both heat and cool the separation column of the second gas chromatograph, and wherein the second thermoelectric cooler is independent of the first thermoelectric cooler; a detector having an inlet and an outlet, the inlet of the detector being coupled to the outlet of the second gas chromatograph; a fluid connection between an outlet of the first gas chromatograph and an inlet of the second gas chromatograph; a three-way valve or a flow splitter coupled in the fluid connection between the outlet of the first gas chromatograph and the inlet of the second gas chromatograph; an additional fluid connection coupled to the three-way valve or flow splitter; and a switch valve coupled to the additional fluid connection.
 2. The apparatus of claim 1, further comprising an additional detector coupled in the additional fluid connection between the switch valve and the three-way valve or flow splitter.
 3. The apparatus of claim 2, further comprising an additional gas chromatograph including an independent thermoelectric cooler, wherein an inlet of the additional gas chromatograph is fluidly coupled to the three-way valve or flow splitter and the outlet of the additional gas chromatograph is fluidly coupled to the additional detector.
 4. The apparatus of claim 2, further comprising a pre-concentrator or a trap coupled in the fluid connection between the outlet of the first gas chromatograph and the inlet of the second gas chromatograph.
 5. The apparatus of claim 4, further comprising a pre-concentrator or a trap coupled in the additional fluid connection between the three-way valve or flow splitter and the inlet of the additional detector.
 6. The apparatus of claim 4, further comprising a switch valve coupled in the fluid connection between the outlet of the first gas chromatograph and the inlet of the second gas chromatograph, the switch valve positioned between the outlet of the pre-concentrator or trap and the inlet of the second gas chromatograph.
 7. The apparatus of claim 6, further comprising a recirculating fluid connection coupled between an inlet of the first gas chromatograph and an outlet of the second gas chromatograph.
 8. The apparatus of claim 7, further comprising a pre-concentrator, a trap, or both coupled in the recirculating fluid connection.
 9. The apparatus of claim 1 wherein at least one of the first and second thermoelectric coolers is integrated with its respective gas chromatograph.
 10. The apparatus of claim 1 wherein at least one of the first and second thermoelectric coolers includes a temperature sensor.
 11. A gas analysis system comprising: a substrate; a cascaded gas chromatograph having a fluid inlet and one or more fluid outlets and being mounted to the substrate, the cascaded gas chromatograph comprising: a first gas chromatograph including a separation column formed in or on a first substrate and a first thermoelectric cooler thermally coupled to the first substrate, wherein the first thermoelectric cooler can both heat and cool the separation column of the first gas chromatograph, a second gas chromatograph including a separation column formed in or on a second substrate and a second thermoelectric cooler thermally coupled to the second substrate, wherein the second thermoelectric cooler can both heat and cool the separation column of the second gas chromatograph, and wherein the second thermoelectric cooler is independent of the first thermoelectric cooler, a detector having an inlet and an outlet, the inlet of the detector being coupled to the outlet of the second gas chromatograph, a fluid connection between an outlet of the first gas chromatograph and an inlet of the second gas chromatograph, a three-way valve or a flow splitter coupled in the fluid connection between the outlet of the first gas chromatograph and the inlet of the second gas chromatograph, an additional fluid connection coupled to the three-way valve or flow splitter, and a switch valve coupled to the additional fluid connection; a control circuit coupled to the cascaded gas chromatograph, wherein the control circuit can communicate with the first and second gas chromatographs and with all detectors in the cascaded gas chromatograph; and a readout circuit coupled to all detectors in the cascaded gas chromatograph and to the control circuit, wherein the readout circuit can communicate with the control circuit and all detectors.
 12. The gas analysis system of claim 11, further comprising an additional detector coupled in the additional fluid connection between the switch valve and the three-way valve or flow splitter.
 13. The gas analysis system of claim 12, further comprising an additional gas chromatograph including an independent thermoelectric cooler, wherein an inlet of the additional gas chromatograph is fluidly coupled to the three-way valve or flow splitter and the outlet of the additional gas chromatograph is fluidly coupled to the additional detector.
 14. The gas analysis system of claim 12, further comprising a pre-concentrator or a trap coupled in the fluid connection between the outlet of the first gas chromatograph and the inlet of the second gas chromatograph.
 15. The gas analysis system of claim 14, further comprising a pre-concentrator or a trap coupled in the additional fluid connection between the three-way valve or flow splitter and the inlet of the additional detector.
 16. The gas analysis system of claim 14, further comprising a switch valve coupled in the fluid connection between the outlet of the first gas chromatograph and the inlet of the second gas chromatograph, the switch valve positioned between the outlet of the pre-concentrator or trap and the inlet of the second gas chromatograph.
 17. The gas analysis system of claim 16, further comprising a recirculating fluid connection coupled between an inlet of the first gas chromatograph and an outlet of the second gas chromatograph.
 18. The gas analysis system of claim 17, further comprising a pre-concentrator, a trap, or both coupled in the recirculating fluid connection.
 19. The gas analysis system of claim 11 wherein at least one of the first and second thermoelectric coolers is integrated with its respective gas chromatograph.
 20. The gas analysis system of claim 11 wherein at least one of the first and second thermoelectric coolers includes a temperature sensor.
 21. The gas analysis system of claim 11 wherein the readout circuit includes thereon an analysis circuit and associated logic to analyze an output signals received from the detectors.
 22. The gas analysis system of claim 21, further comprising an indicator coupled to an output of the analysis circuit to indicate to a user a result of the analysis.
 23. The gas analysis system of claim 11, further comprising a communication interface coupled to the readout circuit to allow the gas analysis system to communicate with an external device.
 24. A process comprising: time-domain separating a plurality of chemicals from a fluid using a cascaded gas chromatograph, the cascaded gas chromatograph comprising: a first gas chromatograph including a separation column formed in or on a first substrate and a first thermoelectric cooler thermally coupled to the first substrate, wherein the first thermoelectric cooler can both heat and cool the separation column of the first gas chromatograph, a second gas chromatograph including a separation column formed in or on a second substrate and a second thermoelectric cooler thermally coupled to the second substrate, wherein the second thermoelectric cooler can both heat and cool the separation column of the second gas chromatograph, and wherein the second thermoelectric cooler is independent of the first thermoelectric cooler, a detector having an inlet and an outlet, the inlet of the detector being coupled to the outlet of the second gas chromatograph, a fluid connection between an outlet of the first gas chromatograph and an inlet of the second gas chromatograph, a three-way valve or a flow splitter coupled in the fluid connection between the outlet of the first gas chromatograph and the inlet of the second gas chromatograph, an additional fluid connection coupled to the three-way valve or flow splitter, and a switch valve coupled to the additional fluid connection; detecting each of the plurality of time-domain-separated chemicals using one or more sensors in all detectors coupled to the cascaded gas chromatograph; and processing signals from each sensor in all detectors to determine the presence and concentration of each chemical.
 25. The process of claim 24, further comprising pre-concentrating the plurality of chemicals in a pre-concentrator before time-domain separation.
 26. The process of claim 25, further comprising filtering the fluid prior to pre-concentrating the chemicals.
 27. The process of claim 24 wherein processing the signals from each sensor in the one or more sensor arrays comprises analyzing the signals to determine the presence and concentration of each chemical.
 28. The process of claim 27 wherein processing the signals further comprises analyzing the presence and concentration of each chemical to determine a meaning.
 29. The process of claim 28, further comprising communicating the presence and concentration of each chemical or communicating the meaning.
 30. The process of claim 22 wherein the cascaded gas chromatograph further comprises: an additional detector coupled in the additional fluid connection between the switch valve and the three-way valve or flow splitter; and an additional gas chromatograph including an independent thermoelectric cooler, wherein an inlet of the additional gas chromatograph is fluidly coupled to the three-way valve or flow splitter and the outlet of the additional gas chromatograph is fluidly coupled to the additional detector. 